This application proposes a career development plan for Dr. A. Cortney Henderson. As a postdoctoral fellow working with Dr. Kim Prisk (mentor), she studied the effects of lung water and gravity on the distribution of pulmonary blood flow using MRI. During the K99 phase, she learned how to apply the multiple inert gas elimination technique (MIGET) in chronic obstructive pulmonary disease (COPD) patients under Dr. Peter Wagner (co-mentor). The research environment at UCSD is excellent, and the Division of Physiology under the leadership of Dr. John West and Dr. Peter Wagner has been among the best in the world for over 30 years. The proposed research plan will study physiological mechanisms associated with the gas exchange defects in COPD, which is characterized by ventilation-perfusion ratio (VA/Q) inequality. Hypoxic pulmonary vasoconstriction (HPV) reduces VA/Q mismatch in COPD. The overall hypothesis is that differing overall VA/Q inequalities, spatial patterns of ventilation and blood flow, and effects of HPV on the distribution of blood flow in COPD reflect whether the disease is predominantly emphysema (lung tissue destruction) or predominantly airway disease. The spatial distribution of pulmonary blood flow, ventilation, and VA/Q will be measured using MRI and overall VA/Q inequality measured using MIGET. COPD patients presenting with predominantly emphysema or predominantly airway disease and age-matched healthy subjects will be studied while breathing air and then a hyperoxic gas to alleviate HPV. The following key hypotheses will be tested: (1) in emphysema predominant patients, the primary cause of regions of high VA/Q is low perfusion due to lung tissue and capillary destruction, the spatial distribution of which is an important determinant of the heterogeneity of ventilation and blood flow, (2) in airway disease predominant patients, the primary cause of regions of low VA/Q is low ventilation due to bronchial obstruction, and (3) the spatial pattern of HPV is an important mechanism contributing to the type of overall VA/Q inequality and spatial heterogeneity of blood flow. We are collaborating with Joe Ramsdell, M.D., UCSD Clinical Study Center PI for the multicenter Genetic Epidemiology of COPD (COPDGene) project funded by NIH, providing access to a large number of well-characterized COPD patients. The overall goal of the COPDGene study is to identify the genetic risk factors in COPD. The aims of COPDGene are highly synergistic with this proposal, thus allowing for characterization of the subtypes of COPD based on physiological mechanisms.